Pyrido [2,1-a] isoquinoline derivatives

ABSTRACT

The present invention provides compounds of formula (I)  
                 
 
     wherein R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are as defined in the specification, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prophylaxis of diseases which are associated with DPP-IV, such as diabetes, particularly non-insulin dependent diabetes mellitus, and impaired glucose tolerance.

BACKGROUND OF THE INVENTION

[0001] The enzyme dipeptidyl peptidase IV (EC.3.4.14.5, abbreviated inthe following as DPP-IV) is involved in the regulation of the activitiesof several hormones. In particular DPP-IV is degrading efficiently andrapidly glucagon like peptide 1 (GLP-1), which is one of the most potentstimulator of insulin production and secretion. Inhibiting DPP-IV wouldpotentiate the effect of endogenous GLP-1, and lead to higher plasmainsulin concentrations. In patients suffering from impaired glucosetolerance and type 2 diabetes mellitus, higher plasma insulinconcentration would moderate the dangerous hyperglycaemia andaccordingly reduce the risk of tissue damage. Consequently, DPP-IVinhibitors have been suggested as drug candidates for the treatment ofimpaired glucose tolerance and type 2 diabetes mellitus (e.g. Vilhauer,WO98/19998). Without disclosing any medical use, Buzas et al., Lab.Chim. Org. V, Fac. Sci., Orleans, Fr. Chim. Ther. (1992), 7(5), 404-7describe synthesis of the compounds of Examples 41 and 42 below.

SUMMARY OF THE INVENTION

[0002] The compounds of the present invention are useful for thetreatment and/or prophylaxis of diabetes or non-insulin dependentdiabetes.

[0003] The present invention provides pyrido[2,1-a]isoquinolinederivatives in accordance with formula (I)

[0004] wherein

[0005] R¹ is lower alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, or lower alkyl substituted by cycloalkyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl;

[0006] R², R³ and R⁴ are each independently hydrogen,, halogen, hydroxy,lower alkyl, lower alkoxy or lower alkenyl, wherein lower alkyl, loweralkoxy and lower alkenyl are optionally substituted by loweralkoxycarbonyl, aryl, substituted aryl, heterocyclyl or substitutedheterocyclyl;

[0007] R⁵ is hydrogen, fluorine, lower alkyl, aryl or substituted aryl;

[0008] R⁶ is hydrogen, lower alkyl or hydroxy-lower alkyl, or

[0009] R⁵ and R⁶ together with the carbon atoms to which they areattached form a five or six membered saturated carbocyclic ring;

[0010] R⁷ is hydrogen, fluorine or lower alkyl; and pharmaceuticallyacceptable salts thereof;

[0011] with the exception ofrac-3β-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminedihydrochloride andrac-3β-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminedihydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

[0012] Novel DPP-IV inhibitors have been found that very efficientlylower plasma glucose levels. Consequently, the compounds of the presentinvention are useful for the treatment and/or prophylaxis of diabetes,particularly non-insulin dependent diabetes mellitus, and/or impairedglucose tolerance, as well as other conditions wherein the amplificationof action of a peptide normally inactivated by DPP-IV gives atherapeutic benefit. Surprisingly, the compounds of the presentinvention can also be used in the treatment and/or prophylaxis of Bowldisease, Colitis Ulcerosa, Morbus Crohn, obesity and/or metabolicsyndrome. Furthermore, the compounds of the present invention can beused as diuretic agents and for the treatment and/or prophylaxis ofhypertension. Unexpectedly, the compounds of the present inventionexhibit improved therapeutic and pharmacological properties compared toother DPP-IV inhibitors known in the art, such as e.g. in context withpharmacokinetics and bioavailability.

[0013] The present invention provides pyrido[2,1-a]isoquinolinederivatives in accordance with formula (I)

[0014] wherein

[0015] R¹ is lower alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, or lower alkyl substituted by cycloalkyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl;

[0016] R², R³ and R⁴ are each independently hydrogen,, halogen, hydroxy,lower alkyl, lower alkoxy or lower alkenyl, wherein lower alkyl, loweralkoxy and lower alkenyl are optionally substituted by loweralkoxycarbonyl, aryl, substituted aryl, heterocyclyl or substitutedheterocyclyl;

[0017] R⁵ is hydrogen, fluorine, lower alkyl, aryl or substituted aryl;

[0018] R⁶ is hydrogen, lower alkyl or hydroxy-lower alkyl, or

[0019] R⁵ and R⁶ together with the carbon atoms to which they areattached form a five or six membered saturated carbocyclic ring;

[0020] R⁷ is hydrogen, fluorine or lower alkyl; and pharmaceuticallyacceptable salts thereof;

[0021] with the exception ofrac-3β-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminedihydrochloride andrac-3β-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminedihydrochloride.

[0022] Unless otherwise indicated, the following definitions are setforth to illustrate and define the meaning and scope of the variousterms used to describe the invention herein. In this specification theterm “lower” is used to mean a group consisting of one to six,preferably of one to four carbon atom(s).

[0023] The term “halogen” refers to fluorine, chlorine, bromine andiodine, preferably to chlorine.

[0024] The term “alkyl”, alone or in combination with other groups,refers to a branched or straight-chain monovalent saturated aliphatichydrocarbon radical of one to twenty carbon atoms, preferably one tosixteen carbon atoms, more preferably one to ten carbon atoms.

[0025] The term “lower-alkyl”, alone or in combination with othergroups, refers to a branched or straight-chain monovalent alkyl radicalof one to six carbon atoms, preferably one to four carbon atoms. Thisterm is further exemplified by radicals such as methyl, ethyl, n-propyl,isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-pentyl, 3-methylbutyl,n-hexyl, 2-ethylbutyl and the like.

[0026] The term “cycloalkyl” refers to a monovalent carbocyclic radicalof three to six carbon atoms. This term is further exemplified byradicals such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,with cyclopropyl being preferred.

[0027] The term “alkoxy” refers to the group R′—O—, wherein R′ is alkyl.The term “lower-alkoxy” refers to the group R′—O—, wherein R′ islower-alkyl. Examples of lower-alkoxy groups are e.g. methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy, with methoxy beingespecially preferred.

[0028] The term “lower alkoxycarbonyl” refers to the group R′—O—C(O)—,wherein R′ is lower alkyl.

[0029] The term “heterocyclyl” refers to a 5- or 6-membered aromatic orsaturated N-heterocyclic residue, which may optionally contain a furthernitrogen or oxygen atom, such as imidazolyl, pyrazolyl, thiazolyl,phenyl, pyridyl, pyrimidyl, morpholino, piperazino, piperidino orpyrrolidino, preferably pyridyl, thiazolyl or morpholino. The term“substituted heterocyclyl” refers to a heterocyclyl that is mono-, di-or tri-substituted, independently, by lower alkyl, lower alkoxy, halo,cyano, azido, amino, di-lower alkyl amino or hydroxy. Preferablesubstituent is lower alkyl, with methyl being preferred.

[0030] The term “aryl” refers to an aromatic monovalent mono- orpolycarbocyclic radical, such as phenyl or naphthyl, preferably phenyl.The term “substituted aryl” refers to an aryl that is mono-, di- ortri-substituted, independently, by lower alkyl, lower alkoxy, halo,cyano, azido, amino, di-lower alkyl amino or hydroxy.

[0031] The term “heteroaryl” refers to a 5- or 6-membered, unsaturatedaromatic monovalent cyclic radical containing one to three, preferablyone or two, heteroatoms independently selected from nitrogen, sulfur andoxygen, with nitrogen being preferred. Examples of heteroaryl residuesare pyrrolyl, pyridinyl and pyrimidinyl, with pyrrolyl and pyridinylbeing preferred. The term “substituted heteroaryl” refers to aheteroalkyl that is mono-, di- or tri-substituted, independently, byhalogen, amino, perfluoro-lower alkyl, lower alkyl or lower alkoxy.

[0032] The term “pharmaceutically acceptable salts” embraces salts ofthe compounds of formula (I) with inorganic or organic acids such ashydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid,phosphoric acid, citric acid, formic acid, maleic acid, acetic acid,fumaric acid, succinic acid, tartaric acid, methanesulphonic acid,salicylic acid, p-toluenesulphonic acid and the like, which are nontoxic to living organisms. Preferred salts with acids are formates,maleates, citrates, hydrochlorides, hydrobromides and methanesulfonicacid salts, with hydrochlorides being especially preferred.

[0033] In one embodiment, the present invention relates to a compound offormula (I) as defined above, wherein R¹ is lower alkyl, aryl,substituted aryl, or lower alkyl substituted by cycloalkyl, aryl orsubstituted aryl; R², R³ and R⁴ are each independently hydrogen,hydroxy, lower alkyl, lower alkoxy or lower alkenyl, wherein loweralkyl, lower alkoxy and lower alkenyl may optionally be substituted bylower alkoxycarbonyl, aryl, substituted aryl, heterocyclyl orsubstituted heterocyclyl; R⁵ and R⁶ are each independently hydrogen,lower alkyl, aryl, substituted aryl, or, together with the carbon atomsto which they are attached form a five or six membered saturatedcarbocyclic ring; and pharmaceutically acceptable salts thereof.

[0034] In another embodiment, the present invention relates to acompound of formula (I) as defined above, wherein R¹ is lower alkyl,phenyl, or cycloalkyl-lower alkyl; R², R³ and R⁴ are each independentlyhydrogen, hydroxy, lower alkoxy; or lower alkoxy substituted by aryl,substituted aryl, heterocyclyl, substituted heterocyclyl, or loweralkoxycarbonyl. Preferable aryl or substituted aryl residues in R², R³and R⁴ are phenyl or phenyl substituted by di-lower alkyl amino orcyano. Preferable heterocyclyl or substituted heterocyclyl residues inR², R³ and R⁴ are morpholino, pyridyl, thiazolyl or thiazolylsubstituted by lower alkyl. Preferable lower alkoxycarbonyl residues inR², R³ and R⁴ are ethoxycarbonlymethoxy.

[0035] In another preferable embodiment, the present invention relatesto a compound of formula (I) as defined above, wherein R¹ is loweralkyl, phenyl, phenyl substituted by lower alkyl or by lower alkoxy, orR¹ is heteroaryl or substituted heteroaryl, such as where the heteroarylresidue is pyrrolyl and pyridinyl, or cycloalkyl-lower alkyl; R², R³ andR⁴ are each independently hydrogen, hydroxy, lower alkoxy; or loweralkoxy substituted by aryl, substituted aryl, heterocyclyl, substitutedheterocyclyl, or lower alkoxycarbonyl; R⁵ is hydrogen, lower alkyl orphenyl mono- or di-substituted by lower alkyl, lower alkoxy or halogen;R⁶ is hydrogen, lower alkyl or hydroxy-lower alkyl; or R⁵ and R⁶together with the carbon atoms to which they are attached form a five orsix membered saturated carbocyclic ring; and R⁷ is hydrogen or loweralkyl

[0036] In one embodiment, residue R¹ is lower alkyl or lower alkylsubstituted by cycloalkyl, preferably cyclopropyl. Preferable loweralkyl residues R¹ are n-propyl, n-butyl, isobutyl, 3-methylbutyl and2-ethylbutyl, most preferred are n-propyl, n-butyl and 3-methylbutyl.

[0037] Preferable lower alkyl substituted by cycloalkyl iscyclopropylmethyl.

[0038] In another embodiment, R¹ is aryl or substituted alkyl,preferably in which the aryl residue is phenyl. Substituted arylresidues R¹ may be mono-, di- or tri-substituted aryl, independently, bylower alkyl, lower alkoxy or hydroxy, preferably by lower alkyl or loweralkoxy. Preferably, aryl residues R¹ are unsubstituted.

[0039] In still another embodiment, R¹ is a heteroaryl or substitutedheteroaryl in which the heteroaryl residue is selected from pyridinyl,pyrimidinyl and pyrrolyl. Preferredare pyridinyl or pyrrolyl.Substituted heteroaryl residues R¹ may be mono-, di- or tri-substitutedheteroaryl, independently, by lower alkyl, lower alkoxy, or hydroxy,preferably by lower alkyl or lower alkoxy. Preferably, heteroarylresidues R¹ are unsubstituted.

[0040] Most preferred R¹ are lower alkyl, preferably n-butyl, orunsubstituted phenyl.

[0041] In one preferable embodiment, residue R² is lower alkoxy,preferably methoxy, hydrogen or hydroxy. Most preferable residue R² ismethoxy.

[0042] In another preferable embodiment, residue R³ is lower alkoxy,with methoxy, ethoxy, propoxy, n-butoxy and isobutoxy being preferred,hydrogen, hydroxy; or lower alkoxy, preferably methoxy or ethoxy,substituted by aryl, substituted aryl, heterocyclyl, substitutedheterocyclyl, or lower alkoxycarbonyl.

[0043] Preferable aryl or substituted aryl substituents in R³ areunsubstituted phenyl or phenyl mono-substituted by di-lower alkyl amino,with dimethylamino being preferred, or by cyano. Most preferable arylsubstituents in R³ is unsubstituted phenyl.

[0044] More preferable residues R³ are lower alkoxy, preferably methoxy,hydrogen or hydroxy. Most preferred residue R³ is methoxy or hydroxy,with methoxy being especially preferred.

[0045] In another preferable embodiment, residue R⁴ is lower alkoxy,preferably methoxy, hydrogen or hydroxy. Most preferable residue R⁴ ishydrogen.

[0046] In one embodiment, R⁵ is hydrogen, lower alkyl, with methyl beingpreferred, or aryl or substituted aryl.

[0047] Preferable aryl or substituted aryl residues R⁵ are unsubstitutedphenyl or phenyl mono-, di- or tri-substituted, independently, by loweralkyl, lower alkoxy or halogen. Most preferable aryl residue R⁵ isunsubstituted phenyl.

[0048] In another embodiment, R⁶ is hydrogen, lower alkyl, with methylbeing preferred, or hydroxy-lower alkyl, with 2-hydroxy-ethyl beingpreferred. Preferably, R⁶ is hydrogen.

[0049] In still another embodiment, R⁵ and R⁶ are hydrogen or, togetherwith the carbon atoms to which they are attached, form a six memberedsaturated carbocyclic ring.

[0050] In one embodiment, R⁷ is hydrogen, in another embodiment R⁷ islower alkyl, preferably methyl.

[0051] Preferred compounds of formula (I) are those selected from thegroup consisting of:

[0052]rac-9,10-dimethoxy-3β-propyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,

[0053]rac-9,10-dimethoxy-3β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0054]rac-3β-cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,

[0055]rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylamine,

[0056]rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2),

[0057]rac-9,10-dimethoxy-3β-propyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2),

[0058]rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylaminechlorohydrate (1:2),

[0059]rac-2β-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-olchlorohydrate (1:2),

[0060]rac-2α-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-olchlorohydrate (1:2),

[0061]rac-2β-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-ol,

[0062]rac-2α-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-ol,and

[0063]rac-9,10-dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine,

[0064] and pharmaceutically acceptable salts thereof.

[0065] Further preferred compounds of formula (I) are those selectedfrom the group consisting of:

[0066]rac-9,10-Dimethoxy-3β-pyrrol-1-yl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0067]rac-9,10-Dimethoxy-3β-p-tolyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,

[0068]rac-9,10-Dimethoxy-3β-p-tolyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0069]rac-9,10-dimethoxy-3β-(3,4-dimethyl-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2),

[0070]rac-9,10-dimethoxy-3β-(3,4-Dimethyl-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2),

[0071]rac-9,10-Dimethoxy-3β-(3-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2),

[0072]rac-9,10-Dimethoxy-3β-(3-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2),

[0073]rac-9,10-Dimethoxy-3β-pyridin-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2),

[0074]rac-9,10-Dimethoxy-3β-pyridin-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2),

[0075]rac-4-(2β-Amino-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-7β-yl)-phenol,

[0076]rac-3β-Butyl-9,10-dimethoxy-6-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine,

[0077]rac-3β-Butyl-7β-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0078]rac-3β-Butyl-7α-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0079]rac-3β-Butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0080]rac-3β-Butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0081]rac-3β-Butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,

[0082] rac-7β-Butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylamine,

[0083]rac-7β-Butyl-11,12-dimethoxy-2,3,4,4aβ6,7,8,9,9aα13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8α-ylamine,

[0084]rac-3β-Butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6α-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine,

[0085]rac-7β-Butyl-11,12-dimethoxy-13b-methyl-2,3,4,4aβ,8,6,7,8,9,9a,13b-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylamine,

[0086]rac-9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0087]rac-9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,

[0088]9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0089]9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,

[0090]9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,

[0091]9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0092](6S)-(2-Amino-3-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-6-yl)-methanol,

[0093]rac-4-(2β-Amino-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-7-yl)-phenol hydrochloride,

[0094]rac-4-(2β-Amino-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-7β-yl)-phenolhydrochloride,

[0095]rac-3β-Butyl-9,10-dimethoxy-6-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylaminehydrochloride,

[0096]rac-3β-Butyl-7β-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride,

[0097]rac-3β-Butyl-7α-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride,

[0098]rac-3β-Butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride,

[0099]rac-3α-Butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminehydrochloride,

[0100]rac-3β-Butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminehydrochloride,

[0101]rac-3β-Butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride,

[0102]rac-3β-Butyl-9,10-dimethoxy-7β-(4-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride,

[0103]rac-3β-Butyl-9,10-dimethoxy-7β-(4-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminehydrochloride,

[0104]rac-3β-Butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride,

[0105]rac-3β-Butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminehydrochloride,

[0106]rac-7β-Butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylaminehydrochloride,

[0107]rac-7β-Butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8α-ylaminehydrochloride,

[0108]rac-3β-Butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6α-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylaminehydrochloride, and pharmaceutically acceptable salts thereof.

[0109] Further preferred compounds of formula (I) are those selectedfrom the group consisting of:

[0110]rac-9,10-dimethoxy-3β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0111]rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylamine,

[0112]rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2),

[0113]rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylaminechlorohydrate (1:2),

[0114]rac-2α-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-olchlorohydrate (1:2),

[0115]rac-2α-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-ol,and

[0116]rac-9,10-dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine,

[0117] and pharmaceutically acceptable salts thereof.

[0118] Especially preferred compounds of formula (I) are those selectedfrom the group consisting of:

[0119]rac-9,10-dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine,

[0120]rac-9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0121]rac-9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,

[0122]9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0123]9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,

[0124]9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,and

[0125]9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0126] and pharmaceutically acceptable salts thereof.

[0127] Most preferred compounds of formula (I) are those selected fromthe group consisting of:

[0128]9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0129]9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,

[0130]9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,and

[0131]9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,

[0132] and pharmaceutically acceptable salts thereof.

[0133] Compounds of formula (I) can have one or more asymmetric carbonatoms and can exist in the form of optically pure enantiomers or asracemates. The invention embraces all of these forms.

[0134] It will be appreciated, that the compounds of formula (I) in thisinvention may be derivatised at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.

[0135] The present invention also relates to a process for themanufacture of compounds of formula (I) as defined above, which processcomprises reducing an oxime of formula (II)

[0136] wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above,

[0137] optionally followed by conversion into a pharmaceuticallyacceptable salt thereof.

[0138] Hydrogenation of the above oxime of formula II can be performedaccording to methods known in the art. For example, the reaction can beperformed in the presence of a catalyst such as Raney nickel, platin orpalladium in an inert solvent, such as ethanol, at a temperature ofabout 20° C. to 80° C.

[0139] Hydroxy groups in the compounds of formula II can be present in aprotected form, for example as a benzyl ether. Such protecting groupscan be removed according to processes known in the art, e.g. in case ofbenzyl ether by catalytic hydrogenation.

[0140] Oximes of formula II are known in the art or can be preparedstarting from ketones of the formula III by methods known in the art andas exemplified or in analogy thereto.

[0141] Compounds of formula (III):

[0142] wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above,

[0143] can be prepared by reacting a compound of the formula (IV):

[0144] wherein R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above,

[0145] with a compound of the formula (V):

[0146] wherein R¹ is as defined above,

[0147] or a compound of the formula (VI):

[0148] wherein R¹ is as defined above.

[0149] Compounds of formula (IV) are known in the art or can be preparedby oxidation of compounds of formula (VIII):

[0150] wherein R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above,

[0151] according to methods known in the art and as exemplified or inanalogy thereto.

[0152] Alternatively, compounds of formula (VII)

[0153] wherein R¹, R², R⁴, R⁵, R⁶ and R⁷ are as defined above and Prepresents an amino protecting group;

[0154] may be reacted with an alcohol

R—OH

[0155] wherein R is lower alkyl substituted by aryl, heterocyclyl orlower alkoxycarbonyl;

[0156] in the presence of triphenylphosphine and di-t-butylazodicarboxylate, followed by deprotection.

[0157] Alternatively, compounds of formula (III) wherein R¹ is aryl orheteroaryl may be prepared by reacting a compound of formula (III)wherein R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above and R¹ ishydrogen (R¹=H) with an aryl halogenide respectively a heteroarylhalogenide

R—X

[0158] wherein R is aryl or heteroaryl and X is chloride, bromide,iodide or triflate; in the presence of a palladium catalyst likepalladium acetate or tetrakis-triphenylphosphine palladium complex, aligand, like tri-tert-butylphosphine or other phosphines, and a baselike sodium tert-butoxide in an inert solvent like tetrahydrofurane atmoderate temperature of 20 to 100° C. (in analogy to the methodsdescribed in J. M. Fox, X. Huang, A. Chieffi, S. L. Buchwald., J. Am.Chem. Soc. 2000, 122, 1360-1370. and M. Kawatsura and J. F. Hartwig, J.Am. Chem. Soc. 1999, 121, 1473-1478).

[0159] Preferred amino protecting groups are t-butyloxycarbonyl (Boc),benzyloxycarbonyl (Z) and 9-fluorenylmethyloxycarbonyl (Fmoc), witht-butyloxycarbonyl (Boc) being especially preferred. Deprotection can beperformed by methods known in the art.

[0160] The invention further relates to compounds of formula (I) asdefined above, when manufactured according to a process as definedabove.

[0161] As described above, the compounds of formula (I) of the presentinvention can be used as medicaments for the treatment and/orprophylaxis of diseases which are associated with DPP-IV such asdiabetes, particularly non-insulin dependent diabetes mellitus, impairedglucose tolerance, Bowl disease, Colitis Ulcerosa, Morbus Crohn,obesity, and/or metabolic syndrome, preferably non-insulin dependentdiabetes mellitus and/or impaired glucose tolerance. Furthermore, thecompounds of the present invention can be used as diuretic agents or forthe treatment and/or prophylaxis of hypertension.

[0162] The invention therefore also relates to pharmaceuticalcompositions comprising a compound as defined above and apharmaceutically acceptable carrier and/or adjuvant.

[0163] Further, the invention relates to compounds as defined above foruse as therapeutic active substances, particularly as therapeutic activesubstances for the treatment and/or prophylaxis of diseases which areassociated with DPP-IV such as diabetes, particularly non-insulindependent diabetes mellitus, impaired glucose tolerance, Bowl disease,Colitis Ulcerosa, Morbus Crohn, obesity, and/or metabolic syndrome,preferably for use as therapeutic active substances for the treatmentand/or prophylaxis of non-insulin dependent diabetes mellitus and/orimpaired glucose tolerance. Furthermore, the invention relates tocompounds as defined above for use as diuretic agents or for use astherapeutic active substances for the treatment and/or prophylaxis ofhypertension.

[0164] In another embodiment, the invention relates to a method for thetreatment and/or prophylaxis of diseases which are associated withDPP-IV such as diabetes, particularly non-insulin dependent diabetesmellitus, impaired glucose tolerance, Bowl disease, Colitis Ulcerosa,Morbus Crohn, obesity, and/or metabolic syndrome, preferably for thetreatment and/or prophylaxis of non-insulin dependent diabetes mellitusand/or impaired glucose tolerance, which method comprises administeringa compound as defined above to a human being or animal. Furthermore, theinvention relates to a method for the treatment and/or prophylaxis asdefined above, wherein the disease is hypertension or wherein a diureticagent has a beneficial effect.

[0165] The invention further relates to the use of compounds as definedabove for the treatment and/or prophylaxis of diseases which areassociated with DPP-IV such as diabetes, particularly non-insulindependent diabetes mellitus, impaired glucose tolerance, Bowl disease,Colitis Ulcerosa, Morbus Crohn, obesity, and/or metabolic syndrome,preferably for the treatment and/or prophylaxis of non-insulin dependentdiabetes mellitus and/or impaired glucose tolerance. Furthermore, theinvention relates to the use as defined above, wherein the disease ishypertension or to the use as diuretic agent.

[0166] In addition, the invention relates to the use of compounds asdefined above for the preparation of medicaments for the treatmentand/or prophylaxis of diseases which are associated with DPP-IV such asdiabetes, particularly non-insulin dependent diabetes mellitus, impairedglucose tolerance, Bowl disease, Colitis Ulcerosa, Morbus Crohn,obesity, and/or metabolic syndrome, preferably for the treatment and/orprophylaxis of non-insulin dependent diabetes mellitus and/or impairedglucose tolerance. Such medicaments comprise a compound as definedabove. Furthermore, the invention relates to the use as defined above,wherein the disease is hypertension or the use for the preparation ofdiuretic agents.

[0167] In context with the methods and uses defined above, the followingdiseases relate to a preferred embodiment: diabetes, particularlynon-insulin dependent diabetes mellitus, impaired glucose tolerance,obesity, and/or metabolic syndrome, preferably non-insulin dependentdiabetes mellitus and/or impaired glucose tolerance.

[0168] The compounds of formula (I) can be manufactured by the methodsgiven below, by the methods given in the Examples or by analogousmethods. Appropriate reaction conditions for the individual reactionsteps are known to the person skilled in the art. Starting materials areeither commercially available or can be prepared by methods analogous tothe methods given below or in the Examples or by methods known in theart.

[0169] The following tests were carried out in order to determine theactivity of the compounds of formula I.

[0170] Activity of DPP-IV inhibitors are tested with natural humanDPP-IV derived from a human plasma pool or with recombinant humanDPP-IV. Human citrate plasma from different donors is pooled, filteredthrough a 0.2 micron membrane under sterile conditions and aliquots of 1ml are shock frozen and stored at −120° C. until used. In thecalorimetric DPP-IV assay 5 to 10 μl human plasma and in thefluorometric assay 1.0 μl of human plasma in a total assay volume of 100μl is used as an enzyme source. The cDNA of the human DPP-IV sequence ofamino acid 31-to 766, restricted for the N-terminus and thetransmembrane domain, is cloned into pichia pastoris. Human DPP-IV isexpressed and purified from the culture medium using conventional columnchromatography including size exclusion and anion and cationchromatography. The purity of the final enzyme preparation of Coomassieblue SDS-PAGE is>95%. In the calorimetric DPP-IV assay 20 ng rec.-hDPP-IV and in the fluorometric assay 2 ng rec-h DPP-IV in a total assayvolume of 100 μl is used as an enzyme source.

[0171] In the fluorogenic assayAla-Pro-7-amido-4-trifluoromethylcoumarin (Calbiochem No 125510) is usedas a substrate. A 20 mM stock solution in 10% DMF/H₂O is stored at −20°C. until use. In IC₅₀ determinations a final substrate concentration of50 μM is used. In assays to determine kinetic parameters as K_(m),V_(max), K_(i), the substrate concentration is varied between 10 μM and500 μM.

[0172] In the colorimetric assay H-Ala-Pro-pNA. HCl (Bachem L-1115) isused as a substrate. A 10 mM stock solution in 10% MeOH/H₂O is stored at−20° C. until use. In IC₅₀ determinations a final substrateconcentration of 200 μM is used. In assays to determine kineticparameters as K_(m), V_(max), K_(i), the substrate concentration isvaried between 100 μM and 2000 μM.

[0173] Fluorescence is detected in a Perkin Elmer LuminescenceSpectrometer LS 50B at an excitation wavelength of 400 nm and anemission wavelength of 505 nm continuously every 15 seconds for 10 to 30minutes. Initial rate constants are calculated by best fit linearregression.

[0174] The absorption of pNA liberated from the calorimetric substrateis detected in a Packard SpectraCount at 405 nM continuously every 2minutes for 30 to 120 minutes. Initial rate constants are calculated bybest fit linear regression.

[0175] DPP-IV activity assays are performed in 96 well plates at 37° C.in a total assay volume of 100 μl. The assay buffer consists of 50 mMTris/HCl pH 7.8 containing 0.1 mg/ml BSA and 100 mM NaCl. Test compoundsare solved in 100% DMSO, diluted to the desired concentration in 10%DMSO/H₂O. The final DMSO concentration in the assay is 1% (v/v).

[0176] At this concentration enzyme inactivation by DMSO is<5%.Compounds are with (10 minutes at 37° C.) and without preincubation withthe enzyme. Enzyme reactions are started with substrate applicationfollowed by immediate mixing.

[0177] IC₅₀ determinations of test compounds are calculated bynon-linear best fit regression of the DPP-IV inhibition of at least 5different compound concentrations. Kinetic parameters of the enzymereaction are calculated at at least 5 different substrate concentrationsand at least 5 different test compound concentrations.

[0178] The preferred compounds of the present invention exhibit IC₅₀values of 1 nM to 10 μM, more preferably of 1-100 nM, as shown in thefollowing table. Example IC₅₀ [μM]  5 0.57 17 0.14 20 0.52 36 0.16 390.62  43b 0.34 44 0.22

[0179] The compounds of formula I and/or their pharmaceuticallyacceptable salts can be used as medicaments, e.g. in the form ofpharmaceutical preparations for enteral, parenteral or topicaladministration. They can be administered, for example, perorally, e.g.in the form of tablets, coated tablets, dragées, hard and soft gelatinecapsules, solutions, emulsions or suspensions, rectally, e.g. in theform of suppositories, parenterally, e.g. in the form of injectionsolutions or infusion solutions, or topically, e.g. in the form ofointments, creams or oils. Oral administration is preferred.

[0180] The production of the pharmaceutical preparations can be effectedin a manner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and/or theirpharmaceutically acceptable salts, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, usualpharmaceutical adjuvants.

[0181] Suitable carrier materials are not only inorganic carriermaterials, but also organic carrier materials. Thus, for example,lactose, corn starch or derivatives thereof, talc, stearic acid or itssalts can be used as carrier materials for tablets, coated tablets,dragées and hard gelatine capsules. Suitable carrier materials for softgelatine capsules are, for example, vegetable oils, waxes, fats andsemi-solid and liquid polyols. Depending on the nature of the activeingredient no carriers might be required for soft gelatine capsules. Inthis case, the soft gel capsule is considered a carrier. Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

[0182] Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

[0183] The dosage of the compounds of formula I can vary within widelimits depending on the disease to be controlled, the age and theindividual condition of the patient and the mode of administration, andwill, of course, be fitted to the individual requirements in eachparticular case. For adult patients a daily dosage of about 1 to 1000mg, especially about 1 to 100 mg, comes into consideration. Depending onseverity of the disease and the precise pharmacokinetic profile thecompound could be administered with one or several daily dosage units,e.g. in 1 to 3 dosage units.

[0184] The pharmaceutical preparations conveniently contain about 1-500mg, preferably 1-100 mg, of a compound of formula I.

[0185] The following Examples serve to illustrate the present inventionin more detail. They are, however, not intended to limit its scope inany manner.

EXAMPLES

[0186] Abbreviations:

[0187] MS=mass spectrometry, ISP=ion spray (positive ion) corresponds toESI (electrospray, positive ion), b.p.=boiling point, m.p.=meltingpoint, aq.=aqueous, r.t.=room temperature.

Example 1

[0188]rac-3β-Butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamineandrac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine

[0189] (i) A solution of 6.8 g of 3,4-dihydro-6,7-dimethoxy-isoquinolinein 70 ml of ethanol is treated with 11.4 g of(2-acetylhexyl)trimethylammonium iodid and heated under reflux for 1.5hours. The reaction mixture is cooled down and treated with a solutionof 6.8 g of potassium hydroxide in 70 ml of water. The ethanol isevaporated and the aq. solution is extracted three times with 80 ml ofdichlormethane. The combined organic solutions are dried over anhydroussodium sulfate and evaporated. The solid red residue is purified bychromatography (silica gel, hexane/ethyl acetate 4:1) and crystallizedfrom isopropyl ether. 7.0 grac-3β-Butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneare obtained, m.p.=117° C.

[0190] (ii) A solution of 5.5 g hydroxylamine hydrochloride in 50 ml ofwater and 20 ml of ethanol is made alkaline (pH 9) with 7.27 ml of Nsodium hydroxide solution and a solution of 3.35 grac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one in 50 ml of ethanol is added. The reaction mixtureis stirred for 45 minutes at 45° C., half concentrated and then cooledto 0° C. The precipitated product is filtered and washed withethanol/water (1:1), subsequently with water. 3.26 grac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime are obtained, m.p.=143-145° C.

[0191] (iii) A suspension of 1.5 grac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime in 40 ml of ethanol and 40 ml of water is treated with 1.25 g of anickel-aluminum alloy and 4.935 ml of an aq. 32% sodium hydroxidesolution are added dropwise. The mixture is stirred thoroughly for fourhours at room temperature, then filtered and washed with ethanol/water(1:1). The filtrate is extracted twice with dichloro-methane and thecombined organic solutions are washed with a saturated solution ofsodium chloride, dried over anhydrous sodium sulfate and evaporated. Thesolid residue is purified by chromatography (silica gel,dichloromethane-methanol/25% ammonium hydroxide (0-16%)). There areobtained (a) 0.38 grac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamineas a resin, MS (ISP) 319.4 (M+H)⁺ and (b) 0.45 grac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamineas a resin, MS (ISP) 319.4 (M+H)⁺.

Examples 2-18

[0192] The following compounds are prepared in analogy to Example 1:

[0193] 2.rac-9,10-Dimethoxy-3β-propyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamineas a resin, MS (ISP) 305.3 (M+H)⁺.

[0194] 3.rac-9,10-Dimethoxy-3β-propyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine as a resin, MS (ISP) 305.3 (M+H)⁺.

[0195] 4.rac-9,10-Dimethoxy-3β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamineas a resin, MS (ISP) 333.3 (M+H)⁺.

[0196] 5.rac-9,10-Dimethoxy-3β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamineas a resin, MS (ISP) 333.3 (M+H)⁺.

[0197] 6.rac-3β-(2-Ethyl-butyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamineas a resin, MS (ISP) 347.5 (M+H)⁺.

[0198] 7.rac-3β-(2-Ethyl-butyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamineas a resin, MS (ISP) 347.5 (M+H)⁺.

[0199] 8.rac-3β-Cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamineas a resin, MS (ISP) 317.3 (M+H)⁺.

[0200] 9.rac-3β-Cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamineas a resin, MS (ISP) 317.3 (M+H)⁺.

[0201] 10.rac-3β-Butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2β-a]isoquinolin-2α-ylamineas a resin, MS (ISP) 347.5 (M+H)⁺.

[0202] 11.rac-3β-Butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamineas an oil, MS (ISP) 359.2 (M+H)⁺.

[0203] 12.rac-3β-Butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamineas an oil, MS (ISP) 359.2 (M+H)⁺.

[0204] 13.rac-3β-Butyl-8,9-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamineas a resin, MS (ISP) 319.5 (M+H)⁺.

[0205] 14.rac-3β-Butyl-8,9-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,MS (ISP) 319.5 (M+H)⁺.

[0206] 15.rac-2β-Amino-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-10-olas an oil, MS (ISP) 305.3 (M+H)⁺.

[0207] 16.rac-2α-Amino-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-10-ol,MS (ISP) 305.3 (M+H)⁺.

[0208] 17.rac-7β-Butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylamineas a solid, MS (ISP) 373.5 (M+H)⁺.

[0209] 18.rac-7β-Butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8α-ylamineas an oil, MS (ISP) 373.5 (M+H)⁺.

[0210] The educts used in Examples 1-18 (compounds of formulae II andIII) which have not been described before can be prepared according tothe procedures described below or in analogy thereto.

[0211] Oxime Derivatives (Compounds of Formula II)

[0212] The following compounds are prepared in analogy to the procedureused for the preparation ofrac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime described above in Example 1:

[0213]rac-9,10-Dimethoxy-3-β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime, MS (ISP): 347.4 (M+H)⁺.

[0214]rac-3β-(2-Ethyl-butyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime, MS (ISP): 361.3 (M+H)⁺.

[0215]rac-3β-Cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime, m.p.=156-158° C.

[0216]rac-3β-Butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime, m.p.=155-159° C.

[0217]rac-7β-Butyl-1,3,4,6,7,13bβ-hexahydro-pyrido[1,2-a]isoquinolin-2-oneoxime, m.p.=140-144° C.

[0218]rac-3β-Butyl-8,9-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime, m.p.=148-150° C.

[0219]rac-3β-Butyl-10-hydroxy-9-methoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime, m.p.=118-120° C.

[0220]rac-7-Butyl-11,12-dimethoxy-1,2,3,4,4a,6,7,9,9a,13b-decahydro-pyrido[1,2-f]phenanthridin-8-oneoxime, m.p.=122-125° C.

[0221] Ketone Derivatives (Compounds of Formula III)

[0222] The following compounds are prepared in analogy to the procedureused for the preparation ofrac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one described above in Example 1:

[0223]rac-3β-Butyl-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one,m.p.=95° C.

[0224]rac-3β-Butyl-8,9-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one,m.p. =89-91° C.

[0225]rac-3β-Butyl-10-hydroxy-9-methoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one,m.p.=136° C.

[0226]rac-7β-Butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8-one,m.p.=157° C.

[0227]rac-3β-Cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one.

[0228] To a solution of 3 g of 3,4-dihydro-6,7-dimethoxy-isoquinoline in10 ml of ethanol is added 2.45 g of3-[(dimethylamino)methyl]-4-cyclopropyl-2-butanone and the mixture isstirred for 18 hours at room temperature. The solids are filtered off,washed with water and re-crystallized from hexane. 2.6 grac-3β-Cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneare obtained, m.p.=99-101° C.

[0229] The educt used above,rac-3-cyclopropylmethyl-4-dimethylamino-butan-2-one (compound of formulaVI), can be prepared by the procedure described below or in analogythereto.

[0230] (i) 36.2 g of ethyl 3-oxo-butyrate are added dropwise withstirring at room temperature to a solution of 7 g of sodium in 160 ml ofethanol. Thereafter, 45.1 g of (bromomethyl)-cyclopropan are added andthe mixture is heated under reflux for two hours. The reaction mixtureis allowed to cool down to room temperature, then it is poured on 500 mlof water and extracted three times with diethylether. After drying onanhydrous sodium sulfate the solvent is evaporated and the residue isdistilled. 38.9 g of ethyl 2-acetyl-cyclopropylpropionate are obtained,b.p.=35-36° C./0.3 mbar.

[0231] (ii) A solution of 3.9 g of potassium hydroxide in 30 ml of wateris added at room temperature to a solution of 11.6 g of ethyl2-acetyl-cyclopropylpropionate. After stirring for four hours at roomtemperature the mixture is neutralized with approx. 5.2 ml ofconcentrated hydrochloric acid and subsequently 5.16 g ofdimethylamine-hydrochloride and 4.82 ml of 36.5% formaldehyde-solutionare added. Thereafter 5.24 ml of concentrated hydrochloric acid areadded within one hour with stirring at room temperature and the mixtureis stirred for 18 hours at the same temperature and extracted twice withdiethylether. After drying on anhydrous sodium sulfate the solvent isevaporated. The residue is purified by chromatography (silica gel,dichloromethane-methanol/25% ammonium hydroxide (0-10%)) andsubsequently distilled (Kugelrohr). 2.9 g ofrac-3-cyclopropylmethyl-4-dimethylamino-butan-2-one are obtained,b.p.=95° C./11 mbar.

Example 19

[0232] To a solution of 380 mg ofrac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminein 40 ml of ethanol is added 2 ml of a saturated solution ofhydrochloric acid in ethanol. The mixture is stirred for one hour atroom temperature and the solids are filtered off. 381 mg ofrac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2) are obtained, MS (ISP) 319.5 (M+H)⁺.

Examples 20-42

[0233] The following compounds are prepared in analogy to Example 19:

[0234] 20.rac-3β-Butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine chlorohydrate (1:2), MS (ISP) 319.5 (M+H)⁺.

[0235] 21.rac-9,10-Dimethoxy-3β-propyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2), m.p.=282-288° C., MS (ISP) 305.4 (M+H)⁺.

[0236] 22.rac-9,10-Dimethoxy-3β-propyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2), m.p.=270-275° C. dec., MS (ISP) 305.3 (M+H)⁺.

[0237] 23.rac-9,10-Dimethoxy-3β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2) as a solid, MS (ISP) 333.3 (M+H)⁺.

[0238] 24.rac-9,10-Dimethoxy-3β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2) as a solid, MS (ISP) 333.4 (M+H)⁺.

[0239] 25.rac-3β-(2-Ethyl-butyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2) as a solid, MS (ISP) 347.5 (M+H)⁺.

[0240] 26.rac-3β-(2-Ethyl-butyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2) as a solid, MS (ISP) 347.4 (M+H)⁺.

[0241] 27.rac-3β-Cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2) as a solid, MS (ISP) 317.3 (M+H)⁺.

[0242] 28.rac-3β-Cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2), m.p.=197-210° C., MS (ISP) 317.3 (M+H)⁺.

[0243] 29.rac-3β-Butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2), m.p.=197-210° C., MS (ISP) 289.3 (M+H)⁺.

[0244] 30.rac-3β-Butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2) as a solid, MS (ISP) 259.3 (M+H)⁺.

[0245] 31.rac-3β-Butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2) as a solid, MS (ISP) 259.2 (M+H)⁺.

[0246] 32.rac-3β-Butyl-8,9-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2), m.p.=116-120° C., MS (ISP) 319.5 (M+H)⁺.

[0247] 33.rac-3β-Butyl-8,9-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2), m.p.=260-265° C., MS (ISP) 319.5 (M+H)⁺.

[0248] 34.rac-2β-Amino-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-10-olchlorohydrate (1:2),m.p.=295-299° C., MS (ISP) 305.4 (M+H)⁺.

[0249] 35.rac-2α-Amino-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-10-olchlorohydrate (1:2), m.p.=322-324° C., MS (ISP) 305.4 (M+H)⁺.

[0250] 36.rac-7β-Butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylaminechlorohydrate (1:2), m.p.=225-233° C., MS (ISP) 373.4 (M+H)⁺.

[0251] 37.rac-7β-Butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8α-ylaminechlorohydrate (1:2), m.p.=215-222° C., MS (ISP) 373.5 (M+H)⁺.

[0252] 38.rac-2β-Amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-olchlorohydrate (1:2), m.p.=230-237° C., MS (ISP) 305.5 (M+H)⁺.

[0253] 39.rac-2α-Amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-olchlorohydrate (1:2), m.p.=230-250° C., MS (ISP) 305.5 (M+H)⁺.

[0254] 40.rac-3β-Butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2), MS (ISP) 289.3 (M+H)⁺.

[0255] 41.rac-3β-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2), MS (ISP) 319.4 (M+H)⁺.

[0256] 42.rac-3β-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2), MS (ISP) 319.4 (M+H)⁺.

Example 43

[0257] A solution of 500 mg ofrac-9-benzyloxy-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime in 60 ml of ethanol is treated with 1 g of a nickel-aluminum alloyand stirred thoroughly for 18 hours at room temperature. The catalyst isfiltered off, washed with ethanol/water (1:1) and the filtrate isevaporated. The residue is purified by chromatography (silica gel,dichloromethane-methanol/25% ammonium hydroxide (0-12%)). There wereobtained (a) 0.08 g ofrac-2β-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-olas a solid, MS (ISP) 305.4 (M+H)⁺ and (b) 0.24 g ofrac-2α-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-olas a solid, MS (ISP) 305.4 (M+H)⁺.

[0258] The educts used in Example 43 are prepared in analogy to thepreparation ofrac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime andrac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneas described in Example 1:

[0259]rac-9-Benzyloxy-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime, m.p.=148-149° C.

[0260]rac-9-Benzyloxy-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one,m.p.=118-119° C.

Examples 44 and 45

[0261] The following compounds were prepared in analogy to Example 1:

[0262] 44.rac-9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine,MS (ISP) 339.4 (M+H)⁺.

[0263] 45.rac-2α-Amino-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-8-olas a resin, MS (ISP) 305.4 (M+H)⁺.

[0264] The educts used in Examples 44 and 45 (compounds of formulae IIand III) which have not been described above can be prepared accordingto the procedures described below or in analogy thereto.

[0265] Oxime Derivatives (Compounds of Formula II)

[0266] The following compound is prepared in analogy to the procedurefor the preparation ofrac-3β-Butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime described in above Example 1:

[0267]rac-9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime, m.p.=232-234° C.

[0268] Ketone Derivatives (Compounds of Formula III)

[0269] The following compounds are prepared in analogy to the procedurefor the preparation ofrac-3β-Butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-onedescribed in above Example 1:

[0270]rac-9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one,m.p.=232-234° C.

[0271]3β-Butyl-8-hydroxy-9-methoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one,m.p.=232-234° C.

Example 4

[0272] A mixture of 4.82 g ofrac-3β-butyl-9-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminein 23 ml of an aq. 48% solution of HBr is stirred 7 h under reflux. Themixture is cooled to 0° C. and an aq. 20% solution of NH₄OH is added toreach a pH=9 followed by NaCl till saturation. The product is extractedwith dichloromethane. The combined organic layers are dried (Na₂SO₄) andthe solvent is evaporated to obtain 4.80 g ofrac-2α-amino-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-olas a solid, MS (ISP) 275.4 (M+H)⁺.

Example 47

[0273]rac-3β-Butyl-9-phenethyloxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2)

[0274] (i) To a solution of 4.50 g ofrac-2α-amino-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-olin 36 ml of anhydrous DMF are added Et₃N (12.78 ml) and di-t-butyldicarbonate (4.44 g). After 3 h stirring water (180 ml) is added and theproduct is extracted with 3 portions of ether. The combined organiclayers are dried (Na₂SO₄) and the solvent is evaporated to obtain thecrude product that is purified by chromatography (silica gel,hexane/ethyl acetate 3:1 to pure ethyl acetate). 3.92 g ofrac-(3β-butyl-9-hydroxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-yl)-carbamicacid tert-butyl ester are obtained as a solid, m.p.=105° C.

[0275] (ii) A mixture of 100 mg ofrac-(3β-butyl-9-hydroxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-yl)-carbamicacid tert-butyl ester, phenethyl alcohol (35 μl) and triphenylphosphineon a polystyrene resin (222 mg, ˜3 mmol triphenyl-phosphine/g resin) indichloromethane (2.6 ml) is prepared and di-t-butyl azodicarboxylate isadded. The mixture is shaken 18 h, then the polymer is filtered away andwashed with dichloromethane and trifluoroacetic acid (2 ml) is added.After 2 h stirring the acid is neutralised by addition of sat. aq.Na₂CO₃ solution. The organic layer is dried (MgSO₄) and the solventevaporated. The product is isolated as its dihydrochloride byprecipitation from a 1.5 M HCl solution in ethyl acetate. 83 mg ofrac-3β-butyl-9-phenethyloxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2) are obtained as a solid, MS (IPS) 379.3 (M+H)⁺.

Examples 48-59

[0276] The following compounds can be prepared in analogy to example 47:

[0277] 48.rac-3β-Butyl-9-ethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2) as a solid, MS (ISP) 303.4 (M+H)³⁰ .

[0278] 49.rac-3β-Butyl-9-propoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2) as a solid, MS (ISP) 317.4 (M+H)⁺.

[0279] 50.rac-9-Butoxy-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminedihyrochloride as a solid, MS (ISP) 331.4 (M+H)⁺.

[0280] 51.rac-3β-Butyl-9-isobutoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2) as a solid, MS (ISP) 331.4 (M+H)⁺.

[0281] 52.rac-9-Benzyloxy-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2) as a solid, MS (ISP) 365.4 (M+H)⁺.

[0282] 53.rac-3β-Butyl-9-[2-(4-dimethylamino-phenyl)-ethoxy]-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2) as a solid, MS (ISP) 422.5 (M+H)⁺.

[0283] 54.rac-4-[2-(2α-Amino-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yloxy)-ethyl]-benzonitrilechlorohydrate (1:2) as a solid, MS (ISP) 404.6 (M+H)⁺.

[0284] 55.rac-3β-Butyl-9-[2-(4-methyl-thiazol-5-yl)-ethoxy]-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2) as a solid, MS (ISP) 400.6 (M+H)⁺.

[0285] 56 .rac-3β-Butyl-9-(pyridin-3-ylmethoxy)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2) as a solid, MS (ISP) 366.4 (M+H)⁺.

[0286] 57.rac-3β-Butyl-9-(pyridin-2-ylmethoxy)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminetrihydrochloride as a solid, MS (ISP) 366.3 (M+H)⁺.

[0287] 58.rac-(2α-Amino-3β-butyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yloxy)-aceticacid ethyl ester chlorohydrate (1:2) as a solid, MS (ISP) 361.4 (M+H)³⁰.

[0288] 59.rac-3β-Butyl-9-(2-morpholin-4-yl-ethoxy)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2) as a solid, MS (ISP) 388.4 (M+H)⁺.

Example 60

[0289]rac-9,10-Dimethoxy-3β-pyrrol-1-yl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine

[0290] (i)2-Amino-9,10-dimethoxy-1,6,7,11b-tetrahydro-4H-pyrido[2,1-a]isoquinoline-3-carboxylicacid ethyl ester

[0291] A solution of3-(1-ethoxycarbonylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propionicacid ethyl ester (Helv. Chim. Acta 1958, 41, 119; 17.1 g, 45.0 mmol) incyclohexane (340 mL) was treated with sodium ethylate (9.67 g, 135 mmol)and heated in an oil bath, and the ethanol formed during the reactionwas removed by distillation over 30 min, while more cyclohexane wasadded in order to keep the reaction volume constant. After cooling thereaction mixture was neutralized with acetic acid and concentrated. Theresidue was dissolved in dichloromethane/water 1:1 and brought to pH 10with concentrated ammonium hydroxide solution. The organic layer wasseparated, dried (MgSO₄), and evaporated. The residue was dissolved inmethanol (270 mL) and ammonium acetate (42.3 g, 548 mmol) was added.After stirring at r.t. for 90 min, the reaction mixture was evaporatedand the residue partitioned between dichloromethane and 1 M aq. sodiumhydroxide solution. The organic layer was dried (MgSO₄), evaporated, andchromatographed (SiO₂, CH₂Cl₂/MeOH/NH₄OH 97.5:2.5:0.25) to afford thetitle compound (9.90 g, 66%). Light yellow solid, MS (ISP) 333.2 (M+H)⁺.

[0292] (ii)rac-3α-tert-Butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-2β-carboxylicacid ethyl ester

[0293] Trifluoroacetic acid (18 mL) was added at 0° C. to a solution of2-amino-9,10-dimethoxy-1,6,7,11b-tetrahydro-4H-pyrido[2,1-a]isoquinoline-3-carboxylicacid ethyl ester (1.00 g, 3.01 mmol) in tetrahydrofuran (9 mL), thenafter 30 min the homogeneous solution was treated with sodiumborohydride (237 mg, 6.02 mmol) and stirred for another 45 min. Thereaction mixture was poured onto 2 M aq. sodium hydroxide solution andextracted with dichloromethane. The organic layer was dried (MgSO₄) andevaporated. The residue was dissolved in dichloromethane (10 mL),di-tert-butyl-dicarbonate (711 mg, 319 mmol) was added, the solution wasstirred at r.t. for 16 h, then evaporated. Chromatography of the residue(SiO₂, CH₂Cl₂/MeOH/NH₄OH 97.5:2.5:0.25) produced the title compound(1.14 g, 87%). Light yellow solid, MS (ISP) 435.4 (M+H)⁺.

[0294] (iii)rac-(2α-tert-Butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-3β-yl)-carbamicacid benzyl ester

[0295] A solution ofrac-2α-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinoline-3β-carboxylicacid ethyl ester (1.00 g, 2.30 mmol) in tetrahydrofuran (10 mL) wastreated with 1 M aq. sodium hydroxide solution (2.30 mL, 2.30 mmol), andthe resultant mixture was stirred at r.t. After 16 h, another portion of1 M aq. sodium hydroxide solution (0.23 mL, 0.23 mmol) was added, andstirring was continued for 4 h. The solvent was then evaporated, theresidue was suspended twice in toluene (50 mL) and concentrated toremove residual water azeotropically. The residue was suspended intoluene (20 mL) and treated with diphenylphosphoryl azide (669 mg, 2.30mmol) and triethylamine (234 mg, 2.30 mmol). The reaction mixture wasstirred at r.t. for 30 min, then heated at 80°60 C. for 45 min, thenbenzyl alcohol (374 mg, 3.47 mmol) was added, and the reaction mixturewas heated at 100°60 C. for 72 h. After cooling and partitioning betweendichloromethane and water, the organic layer was washed with brine,dried (MgSO₄), and evaporated. Chromatography of the residue (SiO₂,CH₂Cl₂/MeOH/NH₄OH 95:5:0.25) produced the title compound (278 mg, 24%).White solid, MS (ISP) 512.5 (M+H)⁺.

[0296] (iv)rac-(3b-Amino-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-yl)-carbamicacid tert-butyl ester

[0297] A solution ofrac-(2α-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-3β-yl)-carbamicacid benzyl ester (275 mg, 0.538 mmol) in acetic acid (10 mL) washydrogenated at r.t. and atmospheric pressure in the presence ofpalladium (10% on activated charcoal, 15 mg). After 30 min, the solventwas evaporated, the residue was treated with toluene (20 mL), thesuspension concentrated and the residue dried in vacuo to afford thetitle compound (247 mg, ca. 85% purity), which was directly used in thenext step. Light yellow solid, MS (ISP) 378.4 (M+H)⁺.

[0298] (v)rac-(9,10-Dimethoxy-3β-pyrrol-1-yl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-yl)-carbamicacid tert-butyl ester

[0299] 2,5-dimethoxytetrahydrofuran (41 mg, 0.30 mmol) was added to asolution ofrac-(3β-amino-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-yl)-carbamicacid tert-butyl ester (120 mg, 0.27 mmol/85% purity) in acetic acid (1.2mL, 21 mmol) and pyridine (0.76 mL, 9.5 mmol). The homogeneous solutionwas heated at 100°60 C. for 105 min, then evaporated, and the residuewas chromatographed (SiO₂, heptane/ethyl acetate gradient) to afford thetitle compound (87 mg, 75%). White solid, MS (ISP) 428.3 (M+H)⁺.

[0300] (vi)rac-9,10-Dimethoxy-3β-pyrrol-1-yl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminerac-(9,10-Dimethoxy-3β-pyrrol-1-yl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-yl)-carbamicacid tert-butyl ester (86 mg, 0.20 mmol) was dissolved in hydrogenchloride solution (4 M in dioxane, 1 mL), stirred at r.t. for 1 h, andevaporated. Chromatography of the residue (SiO₂, CH₂Cl₂/MeOH/NH₄OH95:5:0.25) produced the title compound (58 mg, 88%). White solid, MS(ISP) 328.3 (M+H)⁺.

Examples 61 and 62

[0301] The following compounds are prepared in analogy to Example 1:

[0302] 60.rac-9,10-Dimethoxy-3β-p-tolyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamineas a yellow powder, MS (ISP) 353.3 (M+H)⁺.

[0303] 61.rac-9,10-Dimethoxy-3β-p-tolyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamineas a yellowish powder, MS (ISP) 353.3 (M+H)⁺.

[0304] The educts used in Examples 61 and 62 (compounds of formulae II,III and VI) which have not been described above can be preparedaccording to the procedures described below or in analogy thereto.

[0305] Oxime Derivative (Compound of Formula II)

[0306] The following compound is prepared in analogy to the procedurefor the preparation ofrac-3β-Butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime described in above Example 1:

[0307]rac-9,10-Dimethoxy-3β-p-tolyl-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime as a yellowish powder, MS (ISP) 367.2 (M+H)⁺.

[0308] Ketone Derivative (Compound of Formula III)

[0309] The following compound is prepared in analogy to the procedurefor the preparation ofrac-3β-Butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-onedescribed in above Example 1:

[0310]rac-9,10-Dimethoxy-3β-p-tolyl-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-oneas an off-white powder, MS (ISP) 352.3 (M+H)⁺.

[0311] Ammonium Iodide Derivative (Compound of Formula V)

[0312] A mixture of 4-methylphenylacetone (3.01 g), paraformaldehyde(0.489 g) and dimethylamine hydrochloride (1.49 g) in MeOH (2 ml) isstirred under reflux for 3 h. The reaction mixture is diluted with 20 mlof water and the product is extracted with two portions of ether. Afteraddition of 1 M aqueous NaOH solution, the aqueous layer is extractedwith two more portions of ether. The combined organic layers are dried(Na₂SO₄) and the solvent is evaporated to obtain4-dimethylamino-3-p-tolyl-butan-2-one (compound of formula VI) as ayellowish liquid, MS (ISP) 206.2 (M+H)⁺.4-Dimethylamino-3-p-tolyl-butan-2-one is dissolved in AcOEt (17 ml) andiodomethane (1.46) is added. After 1 h the formed solid is collected byfiltration, washed with AcOEt and dried on the vacuum. 2.61 g oftrimethyl-(3-oxo-2-p-tolyl-butyl)-ammonium iodide are obtained as anoff-white solid, MS (ISP) 220.3 M⁺.

Examples 63 and 64

[0313] (i) 21.5 mg of palladium acetate, 276 mg of sodium tert-butoxideand 23 mg of tri-tert-butylphosphine are placed in a flask, which isevaporated and charged with argon three times. 2 ml of tetrahydrofuraneis added under argon. To this solution 177 mg of 4-bromoxylene and 250mg ofrac-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-one(D. Beke, C. Szantay, Chem. Ber. 95, 2132 (1962)) dissolved in 1 ml oftetrahydrofurane are added. The reaction is stirred at room temperatureunder argon over night. The crude reaction is diluted with diethylether, washed with water and sat. aq. sodium chloride solution. Theorganic layer is dried over sodium sulfate, filtered and the solvent isevaporated. The residue is purified by column chromatography (silicagel, diethyl ether) to yield 92.0 mg ofrac-9,10-dimethoxy-3β-(3,4-dimethyl-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-oneas a light yellow solid. ¹H NMR (CDCl₃): δ=7.16-6.90 (m, 3 H), 6.64 (s,1 H), 6.59 (s, 1 H), 3.93-3.71 (m, 8 H, 2 MeO+2 H), 3.40-3.36 (m, 1 H),3.17-2.6 (m, 7 H), 2.4-2.2 (m, 6 H, 2 Ar—CH₃). MS (ISP): 366.2 (M+H)⁺.

[0314] (ii) To a yellow suspension of 86 mg ofrac-9,10-dimethoxy-3β-(3,4-dimethyl-phenyl)-1,3,4,6,7,11bβ-hexahydro-pyrido[2.1-a]isoquinolin-2-onein 4 ml of ethanol is added 21.2 mg sodium acetate and 18.0 mghydroxylamine hydrochloride. The reaction mixture is stirred for fourhours at room temperature. 4 ml of water and 150 mg of nickel-aluminumalloy are added. 0.7 ml of an aq. 32% sodium hydroxide solution is addeddropwise. The mixture is stirred at room temperature over night,filtered and the solution is extracted three times with dichloromethane.The organic layers are dried over sodium sulfate and the solvent isevaporated. The residue is purified by chromatography (silica gel,dichloro-methane/methanol/sat. aq. ammonia=97/3/0.3). Two products areobtained. They are dissolved independently in dichloromethane andsaturated etheral hydrochloric acid solution is added until a solidprecipitated.

[0315] 63.rac-9,10-dimethoxy-3β-(3,4-dimethyl-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2)

[0316] 14.4 mg of the title compound are obtained as a light yellowsolid. This product is eluted first during chromatography. ¹H NMR(CDCl₃): δ=7.17-6.95 (m, 3 H), 6.70 (s, 1 H), 6.60 (s, 1 H), 3.85 (s, 3H, MeO), 3, 84 (s, 3 H, MeO), 3.6-2.2 (m, 17 H), 2.0-1.8 (m, 1 H).MS(ISP): 367.3 (M+H)⁺.

[0317] 64.rac-9,10-dimethoxy-3β-(3,4-Dimethyl-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2)

[0318] 39.5 mg of the title compound are obtained as a light yellowsolid. This product is eluted second during chromatography. ¹H NMR(CDCl₃): δ=7.15-6.99 (m, 3 H), 6.75 (s, 1 H), 6.60 (s, 1 H), 3.85 (s, 3H, Ar—CH₃), 3.83 (s, 3 H, MeO), 3.4-2.9 (m, 5 H), 2.7-2.2 (m, 12 H). MS(ISP): 367.3 (M+H)⁺.

Examples 65-68

[0319] The following compounds are prepared in analogy to Examples 63and 64:

[0320] 65.rac-9,10-Dimethoxy-3β-(3-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2).

[0321] The title compound was obtained as a light yellow solid. Thisproduct is eluted first during chromatography. ¹H NMR (CDCl₃):δ=7.29-7.24 (m, 1 H), 6.84-6.74 (m, 3 H), 6.70 (s, 1 H), 6.60 (s, 1 H),3.94-3.82 (m, 10 H, 3 MeO+1 H), 3.60-2.36 (m., 10 H), 200-1.95 (m, 1 H).MS (ISP): 369.3 (M+H)³⁰ .

[0322] 66.rac-9,10-Dimethoxy-3β-(3-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2).

[0323] The title compound was obtained as a light yellow solid. Thisproduct is eluted second during chromatography. ¹H NMR (CDCl₃):δ=7.30-7.24 (m, 1 H), 6.89-6.79 (m, 3 H), 6.75 (s, 1 H), 6.60 (s, 1 H),3.85-3.82 (m, 6 H, 2 MeO), 3.82 (m, 4 H, 1 MeO+1 H), 3.4-2.2 (m, 11 H).MS (ISP): 369.3 (M+H)⁺.

[0324] 67.rac-9,10-Dimethoxy-3β-pyridin-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2).

[0325] The title compound is obtained as a light yellow solid. Thisproduct is eluted first during chromatography. ¹H NMR (CDCl₃):δ=8.60-8.57 (m, 1 H), 7.68-7.63 (m, 1 H), 7.27-7.15 (m, 2 H), 6.71 (s, 1H), 6.60 (s, 1 H), 3.85-3.84 (m, 7 H, 2 MeO), 3.8-3.0 (m, 7 H), 2.8-2.6(m, 1 H), 2.45-2.39 (m, 1 H), 2-1.92 (m, 1 H). MS (ISP): 340.3 (M+H)⁺.

[0326] 68.rac-9,10-Dimethoxy-3β-pyridin-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2).

[0327] The title compound was obtained as a light yellow solid. Thisproduct is eluted second during chromatography. ¹H NMR (CDCl₃):δ=8.63-8.61 (m, 1 H), 7.68-7.62 (m, 1 H), 7.26-7.16 (m, 2 H), 6.75 (s, 1H), 6.60 (s, 1 H), 3.87-3.80 (m, 7 H), 3.5-2.5 (m, 11 H). MS (ISP):340.3 (M+H)⁺.

[0328] The following compounds are prepared in analogy to the procedureused for the preparation ofrac-9,10-dimethoxy-3β-(3,4-dimethyl-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-onedescribed above in Examples 63 and 64:

[0329]rac-9,10-dimethoxy-3β-(3-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-oneobtained as a light yellow solid. ¹H NMR (CDCl₃): δ=7.43-6.56 (m, 5 H),3.95-3.72 (m, 11 H, 3 MeO+2 H), 3.45-3.40 (m, 1 H), 3.2-2.6 (m, 8 H). MS(ISP): 368.3 (M+H)⁺.

[0330]rac-9,10-dimethoxy-3β-pyridin-2-yl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-oneobtained as an orange solid. ¹H NMR (CDCl₃): δ=8.38-8.35 (m, 1 H),7.72-7.67 (m, 1 H), 7.07-6.96 (m, 2 H), 6.68 (s, 1 H), 6.62 (s, 1 H),3.93-3.75 (m, 8 H, 2 MeO+2 H), 3.65-3.60 (m, 1 H), 3.40-3.26 (m, 7 H).MS (ISP): 339.3 (M+H)⁺.

Examples 69-81

[0331] The following compounds were prepared in analogy to Example 1:

[0332] 69.rac-4-(2β-Amino-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-7β-yl)-phenol,MS (ISP) 411.5 (M+H)⁺.

[0333] 70.rac-3β-Butyl-9,10-dimethoxy-6-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine,MS (ISP) 333.4 (M+H)⁺.

[0334] 71.rac-3β-Butyl-7β-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,MS (ISP) 429.6 (M+H)⁺.

[0335] 72.rac-3β-Butyl-7α-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,MS (ISP) 429.6 (M+H)⁺.

[0336] 73.rac-3β-Butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,MS (ISP) 455.6 (M+H)⁺.

[0337] 74.rac-3β-Butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,MS (ISP) 347.5 (M+H)⁺.

[0338] 75.rac-3,l-Butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,MS (ISP) 347.5 (M+H)⁺.

[0339] 76 .rac-7β-Butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylamine,MS (ISP) 373.5 (M+H)⁺.

[0340] 77.rac-7β-Butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8α-ylamine,MS (ISP) 373.5 (M+H)⁺.

[0341] 78.rac-3β-Butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6α-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine,MS (ISP) 411.5 (M+H)⁺.

[0342] 79.rac-7β-Butyl-11,12-dimethoxy-13b-methyl-2,3,4,4aβ,6,7,8,9,9a,13b-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylamine,MS (ISP) 387.4 (M+H)⁺.

[0343] 80. rac-9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-yl amine, MS (ISP) 339.3(M+H)⁺.

[0344] 81.rac-9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine, MS (ISP) 339.4 (M+H)⁺.

[0345] Oxime Derivatives (Compound of Formula II)

[0346] The following compounds are prepared in analogy to the procedureused for the preparation ofrac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime described above in Example 1:

[0347]rac-3α-Butyl-9,10-dimethoxy-7α-(4-methoxy-phenyl)-1,3,4,6,7,11bα-hexahydro-pyrido[2,1-a]isoquinolin-2-oneoxime, MS (ISP) 439.5 (M+H)³⁰ .

[0348]rac-7β-Butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8-oneoxime, MS (ISP) 439.5 (M+H)⁺.

[0349] rac-3-Butyl-7-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6-methyl-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one oxime, MS(ISP) 483.5 (M+H)⁺.

[0350] Ketone Derivatives (Compounds of Formula III)

[0351] The following compounds are prepared in analogy to the procedureused for the preparation ofrac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-onedescribed above in Example 1:

[0352]rac-3β-Butyl-7β-(4-hydroxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one,MS (ISP) 410.5 (M+H)⁺.

[0353] rac-3β-Butyl-9,10-dimethoxy-6-methyl-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one, MS(ISP) 332.5 (M+H)⁺.

[0354]rac-3β-Butyl-7β-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one,MS (ISP) 438.5 (M+H)⁺.

[0355]rac-3β-Butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one,MS (ISP) 454.5 (M+H)⁺.

[0356]rac-3β-Butyl-9,10-dimethoxy-7β-(4-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one,MS (ISP) 424.5 (M+H)⁺.

[0357]rac-3β-Butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one,MS (ISP) 346.5 (M+H)⁺.

[0358]rac-7-Butyl-11,12-dimethoxy-1,2,3,4,4a,6,7,9,9a,13b-decahydro-pyrido[1,2-f]phenanthridin-8-one,MS (ISP) 372.5 (M+H)⁺.

[0359]rac-3β-Butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6α-methyl-1,3,4,6,7,11bβ-hexahydro-pyrido[2,1-a]isoquinolin-2-one,MS (ISP) 467.5 (M+H)⁺.

[0360]rac-7β-Butyl-11,12-dimethoxy-13b-methyl-2,3,4,4aβ,6,7,8,9,9a,13b-decahydro-1H-pyrido[1,2-f]phenanthridin-8-one,MS (ISP) 386.5 (M+H)⁺.

[0361] Synthesis of Dihydroisoquinolines (Compounds of Formula IV)

[0362] In analogy to N. Sotomayor, E. Dominguez and E. Lete;Tetrahedron; 51; 12721 (1995).

[0363] rac-6,7-Dimethoxy-4,4-dimethyl-3,4-dihydro-isoquinoline

[0364] A solution of 1.0 g of1,2,3,4-tetrahydro-6,7-dimethoxy-4,4-dimethyl-isoquinoline in 100 ml ofethanol is treated with 2.3 g of iodine and 0.49 g of sodium acetate andheated under reflux for 1 hour. The reaction mixture is cooled down and30 ml of a 10% sodium thiosulphate-solution is added. The mixture isthen diluted with water and extracted with dichloromethane (2×100 ml).The combined organic extracts are washed with brine, dried over sodiumsulfate and concentrated in vacuo. The foamy residue is purified bychromatography (SiO₂, dichloromethane-1% ammonia in methanol, 0-12%) togive the title compound as a yellowish oil (0.72 g), MS (ISP) 220.4(M+H)⁺.

[0365] rac-4-(4-Chloro-phenyl)-6,7-dimethoxy-3,4-dihydro-isoquinoline,MS (ISP) 302.3 (M+H)⁺.

[0366]rac-4-(3,4-Dimethoxy-phenyl)-6,7-dimethoxy-3,4-dihydro-isoquinoline, MS(ISP) 328.4 (M+H)⁺.

[0367] rac-6,7-Dimethoxy-4-(4-methoxy-phenyl)-3,4-dihydro-isoquinoline,MS (ISP) 298.4 (M+H)⁺.

[0368]rac-4α-(3,4-Dimethoxy-phenyl)-6,7-dimethoxy-3α-methyl-3,4-dihydro-isoquinoline,MS (ISP) 342.3 (M+H)⁺.rac-8,9-Dimethoxy-10b-methyl-1,2,3,4,4a,10b-hexahydro-phenanthridine, MS(ISP) 250.4 (M+H)^(+.)

Examples 82-85

[0369] The following enantiopure amines were obtained from thecorresponding enantiopure ketones in analogy to Example 1.

[0370] 82.9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine, MS (ISP) 339.3 (M+H)⁺.

[0371] 83.9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-yl amine, MS (ISP) 339.3 (M+H)⁺.

[0372] 84.9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-yl amine, MS (ISP) 339.3 (M+H)⁺.

[0373] 85.9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine, MS (ISP) 339.3 (M+H)⁺.

[0374] Ketone Derivatives (Compounds of Formula III)

[0375](−/trans)-9,10-Dimethoxy-3-phenyl-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one[α]_(D) ²⁰=−46.3(c0.28, CHCl₃,λ=436 nm) and(+/trans)-9,10-Dimethoxy-3-phenyl-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one([α]_(D) ²⁰=+44.8(c0.28, CHCl₃,λ=436 nm) were obtained by chiralseparation of the corresponding racemic mixturerac-9,10-Dimethoxy-3-phenyl-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-oneusing Chiracel OD (20 μm, 25 cm×5 cm), eluting with Heptan/ EtOH/ DEA(80/20/0.01 at 80 ml/min).

Example 86

[0376](6S)-(2-Amino-3-butyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-6-yl)-methanolwas obtained from(6S)-3-Butyl-6-hydroxymethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-onein analogy to Example 1.

[0377](6S)-3-Butyl-6-hydroxymethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one.

[0378] (i) A solution of 1.4 g(S)-6,7-Dimethoxy-3-tert-butyldimethoxysiloxymethyl-3,4-dihydroisoquinoline(Y. Haraguchi, Kozima, S. Yamaguchi, R. Tetrahedron Asymmetry, 1996, 7,443) in 8.5 ml of methanol is treated with 1.37 g of(2-acetylhexyl)trimethyl-ammonium iodid and heated under reflux for 4hours. After such time another 0.7 g of (2-acetylhexyl)trimethylammoniumiodid was added and the reaction mixture was stirred under reflux foranother 20 hours. The reaction mixture is cooled down and treated with asolution of 0.76 g of potassium hydroxide in 70 ml of water. The ethanolis evaporated and the aq. solution is extracted three times with 15 mlof dichloromethane.

[0379] The combined organic extracts are dried over anhydrous sodiumsulfate and evaporated. The residue is purified by chromatography(silica gel, hexane/ethyl acetate 0-100%) to give 1.95 g of(6S)-3-Butyl-3-hydroxy-6-tert-butyldimethoxysiloxymethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-oneas a mixture of diasteomers, MS (ISP) 462.5 (M+H)⁺.

[0380] (ii) To a solution of 0.40 g of(6S)-3-Butyl-3-hydroxy-6-tert-butyldimethoxy-siloxymethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-onein 13 ml of THF at 0° C. was slowly added a solution of 1.78 ml oftetrabutylammonium fluoride (1M in THF). The reaction mixture wasstirred for 2 hours keeping the temperature between 0-5° C. The reactionmixture was poured into ice cooled water (49 ml) and then extracted twotimes with 30 ml of ethyl acetate. The organic extracts were dried overanhydrous sodium sulfate and concentrated in vacuo. The residue was thenpurified by chromatography (silica gel, hexane/ethyl acetate 0-70%) togive 0.30 g of(6S)-3-Butyl-6-hydroxymethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one, MS (ISP) 348.3 (M+H)⁺.

Examples 87-102

[0381] The Following Compounds Were Prepared in Analogy to Example 19:

[0382] 87.rac-4-(2β-Amino-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-7-yl)-phenolhydrochloride, MS (ISP) 411.5 (M+H)⁺.

[0383] 88.rac-4-(2β-Amino-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-7β-yl)-phenolhydrochloride, MS (ISP) 411.4 (M+H)⁺.

[0384] 89.rac-3β-Butyl-9,10-dimethoxy-6-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylaminehydrochloride, MS (ISP) 333.4 (M+H)⁺.

[0385] 90.rac-3β-Butyl-7β-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride, MS (ISP) 429.6 (M+H)⁺.

[0386] 91.rac-3β-Butyl-7α-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11b,β-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine hydrochloride, MS(ISP) 429.6 (M+H)⁺.

[0387] 92.rac-3β-Butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride, MS (ISP) 455.6 (M+H)⁺.

[0388] 93.rac-3α-Butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine hydrochloride, MS (ISP) 455.6 (M+H)⁺.

[0389] 94.rac-3β-Butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminehydrochloride, MS (ISP) 455.6 (M+H)⁺.

[0390] 95.rac-3β-Butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride, MS (ISP) 455.6 (M+H)⁺.

[0391] 96.rac-3β-Butyl-9,10-dimethoxy-7β-(4-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride, MS (ISP) 425.5 (M+H)⁺.

[0392] 97.rac-3β-Butyl-9,10-dimethoxy-7β-(4-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminehydrochloride, MS (ISP) 425.5 (M+H)⁺.

[0393] 98.rac-3β-Butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride, MS (ISP) 347.5 (M+H)⁺.

[0394] 99.rac-3β-Butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminehydrochloride, MS (ISP) 347.5 (M+H)⁺.

[0395] 100.rac-7β-Butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylaminehydrochloride, MS (ISP) 373.5 (M+H)⁺.

[0396] 101.rac-7β-Butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8α-ylaminehydrochloride, MS (ISP) 373.5 (M+H)⁺.

[0397] 102.rac-3β-Butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6α-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylaminehydrochloride, MS (ISP) 411.5 (M+H)⁺.

Galenical Examples

[0398] Example A

[0399] Film coated tablets containing the following ingredients can bemanufactured in a conventional manner: Ingredients Per tablet Kernel:Compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5mg 43.5 mg Lactose hydrous 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mgSodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg(Kernel Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methylcellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3mg 2.6 mg Iron oxyde (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8 mg 1.6 mg

[0400] The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidon in water. The granulate is mixed with sodium starchglycolate and magnesium stearate and compressed to yield kernels of 120or 350 mg respectively. The kernels are lacquered with an aq.solution/suspension of the above mentioned film coat.

[0401] Example B

[0402] Capsules containing the following ingredients can be manufacturedin a conventional manner: Ingredients Per capsule Compound of formula(I) 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg

[0403] The components are sieved and mixed and filled into capsules ofsize 2.

[0404] Example C

[0405] Injection solutions can have the following composition: Compoundof formula (I) 3.0 mg Polyethylene Glycol 400 150.0 mg Acetic Acid q.s.ad pH 5.0 Water for injection solutions ad 1.0 ml

[0406] The active ingredient is dissolved in a mixture of PolyethyleneGlycol 400 and water for injection (part). The pH is adjusted to 5.0 byAcetic Acid. The volume is adjusted to 1.0 ml by addition of theresidual amount of water. The solution is filtered, filled into vialsusing an appropriate overage and sterilized.

[0407] Example D

[0408] Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner: Capsule contents Compound offormula (I) 5.0 mg Yellow wax 8.0 mg Hydrogenated Soya bean oil 8.0 mgPartially hydrogenated plant oils 34.0 mg Soya bean oil 110.0 mg Weightof capsule contents 165.0 mg Gelatin capsule Gelatin 75.0 mg Glycerol85% 32.0 mg Karion 83 8.0 mg (dry matter) Titan dioxide 0.4 mg Ironoxide yellow 1.1 mg

[0409] The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

[0410] Example E

[0411] Sachets containing the following ingredients can be manufacturedin a conventional manner: Compound of formula (I) 50.0 mg Lactose, finepowder 1015.0 mg Microcristalline cellulose (AVICEL PH 102) 1400.0 mgSodium carboxymethyl cellulose 14.0 mg Polyvinylpyrrolidon K 30 10.0 mgMagnesium stearate 10.0 mg Flavoring additives 1.0 mg

[0412] The active ingredient is mixed with lactose, microcristallinecellulose and sodium carboxymethyl cellulose and granulated with amixture of polyvinylpyrrolidon in water. The granulate is mixed withmagnesium stearate and the flavouring additives and filled into sachets.

What is claimed is:
 1. A Compound of formula (I)

wherein R¹ is lower alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, or lower alkyl substituted by cycloalkyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R², R³ and R⁴are each independently hydrogen, halogen, hydroxy, lower alkyl, loweralkoxy or lower alkenyl, wherein lower alkyl, lower alkoxy and loweralkenyl are optionally substituted by lower alkoxycarbonyl, aryl,substituted aryl, heterocyclyl or substituted heterocyclyl. R⁵ ishydrogen, fluorine, lower alkyl, aryl or substituted aryl; R⁶ ishydrogen, lower alkyl or hydroxy-lower alkyl, or R⁵ and R⁶ together withthe carbon atoms to which they are attached form a five or six memberedsaturated carbocyclic ring; R⁷ is hydrogen, fluorine or lower alkyl; andpharmaceutically acceptable salts thereof; with the exception ofrac-3β-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminedihydrochloride andrac-3β-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine dihydrochloride.
 2. The compound according toclaim 1, wherein R¹ is lower alkyl, aryl, substituted aryl, or loweralkyl substituted by cycloalkyl, aryl or substituted aryl; R², R³ and R⁴are each independently hydrogen, hydroxy, lower alkyl, lower alkoxy orlower alkenyl, wherein lower alkyl, lower alkoxy and lower alkenyl areoptionally substituted by lower alkoxycarbonyl, aryl, substituted aryl,heterocyclyl, or substituted heterocyclyl; R⁵ and R⁶ are eachindependently hydrogen, lower alkyl, aryl, substituted aryl, or,together with the carbon atoms to which they are attached form a five orsix membered saturated carbocyclic ring.
 3. The compound according toclaim 1, wherein R¹ is lower alkyl, phenyl, or lower alkyl substitutedby cycloalkyl.
 4. The compound according to claim 3, wherein R¹ is loweralkyl or lower alkyl substituted by cycloalkyl.
 5. The compoundaccording to claim 1, wherein R¹ is a heteroaryl or substitutedheteroaryl in which the heteroaryl residue is selected from pyrrolyl andpyridinyl.
 6. The compound according to claim 1, wherein R², R³ and R⁴are each independently hydrogen, hydroxy, lower alkoxy; or lower alkoxysubstituted by aryl, substituted aryl, heterocyclyl, substitutedheterocyclyl, or lower alkoxycarbonyl.
 7. The compound according toclaim 6, wherein R², R³ and R⁴ are each independently lower alkoxysubstituted by phenyl or phenyl substituted by di-lower alkyl amino orcyano.
 8. The compound according to claim 6, wherein R² is lower alkoxy.9. The compound according to claim 6, wherein R³ is lower alkoxy,hydrogen, hydroxy; or lower alkoxy substituted by aryl, substitutedaryl, heterocyclyl, substituted heterocyclyl or lower alkoxycarbonyl.10. The compound according to claim 9, wherein R³ is lower alkoxy,hydrogen or hydroxy.
 11. The compound according to claim 6, wherein R⁴is lower alkoxy, hydrogen or hydroxy.
 12. The compound according toclaim 1, wherein R⁵ and R⁶ are hydrogen or, together with the carbonatoms to which they are attached, form a six membered saturatedcarbocyclic ring.
 13. The compound according to claim 1, selected fromthe group consisting of:rac-9,10-dimethoxy-3β-propyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,rac-9,10-dimethoxy-3,β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,rac-3β-cyclopropylmethyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylamine,rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2),rac-9,10-dimethoxy-3β-propyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2),rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylaminechlorohydrate (1:2),rac-2β-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-olchlorohydrate (1:2),rac-2α-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-olchlorohydrate (1:2),rac-2β-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-ol,rac-2α-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-ol,andrac-9,10-dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine.14. The compound according to claim 1, selected from the groupconsisting of:rac-9,10-dimethoxy-3β-(3-methyl-butyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylamine,rac-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2),rac-7β-butyl-11,12-dimethoxy-2,3,4,4a,6,7,8,9,9a,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylaminechlorohydrate (1:2),rac-2α-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-olchlorohydrate (1:2),rac-2α-amino-3β-butyl-10-methoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-ol,andrac-9,10-dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine.15. The compound according to claim 1, selected from the groupconsisting of:rac-9,10-Dimethoxy-3β-pyrrol-1-yl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,rac-9,10-Dimethoxy-3,β-p-tolyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,rac-9,10-Dimethoxy-3β-p-tolyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinotin-2α-ylamine,rac-9,10-dimethoxy-3β-(3,4-dimethyl-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2),rac-9,10-dimethoxy-3β-(3,4-Dimethyl-phenyl)1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2),rac-9,10-Dimethoxy-3β-(3-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2),rac-9,10-Dimethoxy-3β-(3-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2),rac-9,10-Dimethoxy-3β-pyridin-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminechlorohydrate (1:2),rac-9,10-Dimethoxy-3β-pyridin-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminechlorohydrate (1:2),rac-4-(2β-Amino-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-7β-yl)-phenol,rac-3β-Butyl-9,10-dimethoxy-6-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine,rac-3β-Butyl-7β-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,rac-3β-Butyl-7α(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,rac-3β-Butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,rac-3β-Butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine,rac-3β-Butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,rac-7β-Butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylamine,rac-7β-Butyl-11,12-dimethoxy-2,3,4,4aβ,6,6,7,8,9,9aα13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8α-ylamine,rac-3β-Butyl-7α(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6α-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine,rac-7β-Butyl-11,12-dimethoxy-13b-methyl-2,3,4,4aβ,6,7,8,9,9a,13b-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylamine,rac-9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-yl amine,rac-9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylamine, 9,10-Dimethoxy-3α-phenyl-1,3,4,6,7,11bα-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-yl amine, 9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine,9,10-Dimethoxy-3β-phenyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-yl amine,(6S)-(2-Amino-3-butyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-6-yl)-methanol,rac-4-(2β-Amino-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-7-yl)-phenolhydrochloride,rac-4-(2β-Amino-3β-butyl-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-7β-yl)-phenolhydrochloride,rac-3β-Butyl-9,10-dimethoxy-6-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylaminehydrochloride,rac-3β-Butyl-7β-(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride, rac-3β-Butyl-7α(4-chloro-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride,rac-3β-Butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride,rac-3α-Butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylamine hydrochloride,rac-3β-Butyl-7β-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminehydrochloride,rac-3β-Butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride,rac-3β-Butyl-9,10-dimethoxy-7β-(4-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride,rac-3β-Butyl-9,10-dimethoxy-7β-(4-methoxy-phenyl)-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminehydrochloride,rac-3β-Butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2α-ylaminehydrochloride,rac-3β-Butyl-9,10-dimethoxy-7,7-dimethyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2β-ylaminehydrochloride,rac-7β-Butyl-11,12-dimethoxy-2,3,4,4aβ,,6,7,8,9,9aα,13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8β-ylaminehydrochloride,rac-7β-Butyl-11,12-dimethoxy-2,3,4,4aβ,6,7,8,9,9aα13bβ-decahydro-1H-pyrido[1,2-f]phenanthridin-8α-ylaminehydrochloride, andrac-3β-Butyl-7α-(3,4-dimethoxy-phenyl)-9,10-dimethoxy-6α-methyl-1,3,4,6,7,11bβ-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylaminehydrochloride.
 16. A pharmaceutical composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable carrier.
 17. Amethod for the treatment or prophylaxis of diabetes or non-insulindependent diabetes mellitus, which comprises administering to a patientin need of treatment a compound according to claim 1 in an amount offrom about 1 to 1000 mg.
 18. The method according to claim 17, whereinthe amount administered is a daily dosage of from about 1 to 100 mg.